PMID- 32060513
OWN - NLM
STAT- MEDLINE
DCOM- 20220224
LR  - 20220224
IS  - 1537-6613 (Electronic)
IS  - 0022-1899 (Print)
IS  - 0022-1899 (Linking)
VI  - 224
IP  - 7
DP  - 2021 Oct 13
TI  - Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate 
      Latent Pathogenic Human Polyomavirus Replication.
PG  - 1160-1169
LID - 10.1093/infdis/jiaa071 [doi]
AB  - BACKGROUND: Human polyomaviruses can reactivate in transplant patients, causing 
      nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, 
      pruritic, rash or trichodysplasia spinulosa. Sirolimus and related mechanistic 
      target of rapamycin (mTOR) inhibitors are transplant immunosuppressants. It is 
      unknown if they directly reactivate polyomavirus replication from latency beyond 
      their general effects on immunosuppression. METHODS: In vitro expression and 
      turnover of large T (LT) proteins from BK virus, JC virus (JCV), Merkel cell 
      polyomavirus (MCV), human polyomavirus 7 (HPyV7), and trichodysplasia spinulosa 
      polyomavirus (TSV) after drug treatment were determined by immunoblotting, 
      proximity ligation, replicon DNA replication, and whole virus immunofluorescence 
      assays. RESULTS: mTOR inhibition increased LT protein expression for all 5 
      pathogenic polyomaviruses tested. This correlated with LT stabilization, decrease 
      in the S-phase kinase-associated protein 2 (Skp2) E3 ligase targeting these LT 
      proteins for degradation, and increase in virus replication for JCV, MCV, TSV, 
      and HPyV7. Treatment with sirolimus, but not the calcineurin inhibitor 
      tacrolimus, at levels routinely achieved in patients, resulted in a 
      dose-dependent increase in viral DNA replication for BKV, MCV, and HPyV7. 
      CONCLUSIONS: mTOR inhibitors, at therapeutic levels, directly activate 
      polyomavirus replication through a Skp2-dependent mechanism, revealing a 
      proteostatic latency mechanism common to polyomaviruses. Modifying existing drug 
      regimens for transplant patients with polyomavirus-associated diseases may reduce 
      symptomatic polyomavirus replication while maintaining allograft-sparing 
      immunosuppression.
CI  - (c) The Author(s) 2020. Published by Oxford University Press for the Infectious 
      Diseases Society of America.
FAU - Alvarez Orellana, Jennifer
AU  - Alvarez Orellana J
AD  - Cancer Virology Program, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
AD  - Department of Microbiology and Molecular Genetics, University of Pittsburgh, 
      Pittsburgh, Pennsylvania, USA.
FAU - Kwun, Hyun Jin
AU  - Kwun HJ
AD  - Cancer Virology Program, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
AD  - Department of Microbiology and Immunology, Pennsylvania State University, 
      Hershey, Pennsylvania, USA.
FAU - Artusi, Sara
AU  - Artusi S
AD  - Department of Microbiology and Molecular Genetics, University of Pittsburgh, 
      Pittsburgh, Pennsylvania, USA.
FAU - Chang, Yuan
AU  - Chang Y
AD  - Cancer Virology Program, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
AD  - Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
FAU - Moore, Patrick S
AU  - Moore PS
AD  - Cancer Virology Program, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
AD  - Department of Microbiology and Molecular Genetics, University of Pittsburgh, 
      Pittsburgh, Pennsylvania, USA.
LA  - eng
GR  - R01 CA232604/CA/NCI NIH HHS/United States
GR  - R35 CA197463/CA/NCI NIH HHS/United States
GR  - P30 CA047904/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Infect Dis
JT  - The Journal of infectious diseases
JID - 0413675
RN  - 0 (DNA, Viral)
RN  - 0 (MTOR Inhibitors)
RN  - 0 (S-Phase Kinase-Associated Proteins)
RN  - 0 (SKP2 protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - BK Virus
MH  - DNA Replication/*drug effects
MH  - DNA, Viral
MH  - Humans
MH  - JC Virus
MH  - MTOR Inhibitors/*pharmacology
MH  - Merkel cell polyomavirus
MH  - Polyomavirus/*drug effects/genetics
MH  - Polyomavirus Infections/drug therapy
MH  - *S-Phase Kinase-Associated Proteins
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Tacrolimus/pharmacology
MH  - Virus Replication/*drug effects
PMC - PMC8514189
OTO - NOTNLM
OT  - BKV
OT  - MCPyV
OT  - Skp2
OT  - human polyomavirus
OT  - large T antigen
OT  - latency
OT  - mTOR inhibition
OT  - proteostasis
OT  - sirolimus
OT  - tacrolimus
EDAT- 2020/02/16 06:00
MHDA- 2022/02/25 06:00
PMCR- 2020/02/15
CRDT- 2020/02/16 06:00
PHST- 2019/11/29 00:00 [received]
PHST- 2020/02/13 00:00 [accepted]
PHST- 2020/02/16 06:00 [pubmed]
PHST- 2022/02/25 06:00 [medline]
PHST- 2020/02/16 06:00 [entrez]
PHST- 2020/02/15 00:00 [pmc-release]
AID - 5736392 [pii]
AID - jiaa071 [pii]
AID - 10.1093/infdis/jiaa071 [doi]
PST - ppublish
SO  - J Infect Dis. 2021 Oct 13;224(7):1160-1169. doi: 10.1093/infdis/jiaa071.